P6: RATIONAL DESIGN OF NOVEL NATURAL PRODUCT-DERIVED CANNABINOID LIGANDS

P6：新型天然产物衍生的大麻素配体的合理设计

• 批准号: 8167946
• 负责人: Robert J Doerksen
• 金额: $ 17.24万
• 依托单位: UNIVERSITY OF MISSISSIPPI
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8167946
• 关键词: Agonist; Biological Factors; CNR2 gene; Cannabinoids; Categories; Computer Retrieval of Information on Scientific Projects Database; Computing Methodologies; Data; Development; Docking; Ensure; Funding; Grant; Institution; Ligands; Literature; Modeling; Modification; Molecular; Quantitative Structure-Activity Relationship; Research; Research Personnel; Resources; Screening procedure; Source; Study models; United States National Institutes of Health; base; design; improved; in vitro activity; novel; pharmacophore; receptor; three dimensional structure; virtual

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. For this proposal, the hypothesis is that intensive ligand-based computational methods will yield improved understanding of the requirements for effective and selective CB1/CB2 inhibition and will provide a rational guide for novel CB ligand development. The specific aims are: Aim 1. Develop four classes of pharmacophore models for CB1 and CB2 agonists and antagonists, based on all CB ligand and activity data available in the literature. The pharmacophore models will be cross-compared to gain understanding of requirements for receptor selectivity. Aim 2. Use the best pharmacophore models from Aim 1 for virtual screening to identify novel CB ligands in the different categories. Aim 3. Using CB1 and CB2 in vitro activity data for novel ligands, develop quantitative structure-activity relationship (QSAR) models to aid understanding of the molecular basis for the activity and selectivity and to provide a rational guide to modification of ligands for enhanced activity and selectivity. Though not specifically emphasized in the original proposal, we are proceeding with limited modeling of the CB1 and CB2 receptor three-dimensional structure and ligand docking studies, in order to aid the ligand-based modeling studies of Aims 1 and 3 and to ensure that we have as comprehensive an approach as possible to the rational search for novel CB ligands.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 中心，不一定是研究者的机构。 对于该提案，假设基于密集配体的计算方法将加深对有效和选择性 CB1/CB2 抑制的要求的理解，并将为新型 CB 配体的开发提供合理的指导。具体目标是： 目标 1. 根据文献中提供的所有 CB 配体和活性数据，开发 CB1 和 CB2 激动剂和拮抗剂的四类药效团模型。药效团模型将进行交叉比较，以了解受体选择性的要求。 目标 2. 使用目标 1 中的最佳药效团模型进行虚拟筛选，以识别不同类别中的新型 CB 配体。 目标 3. 使用新型配体的 CB1 和 CB2 体外活性数据，开发定量构效关系 (QSAR) 模型，以帮助理解活性和选择性的分子基础，并为配体修饰以增强活性提供合理的指导和选择性。 虽然在最初的提案中没有特别强调，但我们正在进行CB1和CB2受体三维结构的有限建模和配体对接研究，以帮助目标1和3的基于配体的建模研究，并确保我们拥有尽可能全面的方法来合理寻找新型 CB 配体。